Action Points

Polycythemia vera (PV) patients with any of three key features -- history of prior hydroxyurea (HU) use, phlebotomy requirements, and palpable splenomegaly -- have significant PV-associated symptoms, and symptom burden is still substantial independent of the three key features.

PV is a myeloproliferative neoplasm that evolves from dysregulated clonal erythropoiesis, and is recognized for its distinct molecular profile, burdensome symptoms, predilection for thrombosis, and capacity to transform into acute myelogenous leukemia or myelofibrosis.

Patients with polycythemia vera (PV) who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly have significant PV-associated symptoms, an international prospective study has demonstrated. But the study also showed that many PV symptoms remain severe independent of the number of features present, according to Ruben A. Mesa, MD, of the Mayo Clinic, Scottsdale, AZ and colleagues.

"The results of this study clearly demonstrate that the symptom burden in patients with PV is substantial, independent of whether a patient has used HU, has received phlebotomy, or has splenomegaly," the investigators reported online in the Journal of Clinical Oncology.

Although the phase III prospective Randomized Study of Efficacy and Safety in Polycythemia Vera with JAK Inhibitor INCB018424 versus Best Supportive Care (RESPONSE) demonstrated that the JAK2 inhibitor ruxolitinib effectively alleviated symptoms and controlled hematocrit in PV patients with all three features, the current study suggests that PV patients who have only one or two features also may benefit from JAK2 inhibitor treatment.

"Patients with PV with any of the key three features -- failed hydrea, enlarged spleen, actively needing phlebotomy -- had significant symptom burden and unmet needs," Mesa said in an interview. "Based on these findings, any PV patients with any of these three features might benefit from JAK inhibition or interferon therapy," Mesa told MedPage Today.

A myeloproliferative neoplasm (MPN) that evolves from dysregulated clonal erythropoiesis, PV is recognized for its distinct molecular profile (JAKV617F), burdensome symptoms, predilection for thrombosis, and capacity to transform into acute myelogenous leukemia (AML) or myelofibrosis (MF), noted the investigators.

In the study, 1,334 patients with PV who had characterized symptom burden were recruited from international academic, private, and government medical institutions during routine office visits. This was carried out using a format previously published for validation of the MPN symptom assessment form (MPN-SAF) and through an online international survey (MPN 2014 fatigue project).

Patient demographics, laboratory data, and the presence of splenomegaly by disease feature including known HU use, known phlebotomy requirements, and the presence of splenomegaly were thoroughly assessed.

The study showed that the presence of each feature of PV was individually associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persisted independent of PV risk category. In addition, it revealed that symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S), said the investigators.

Based on the number of features present, there was a statistical difference in risk scores, said the investigators. "Positive associations were also noted between the severity of thrombocythemia, leukocytosis, or prior hemorrhage and the presence of multiple features, as demonstrated by patients in the PV-HUPS subgroup," they reported.

Weight loss and fevers were least likely to differ between feature groups and their associated controls or to vary by the number of features possessed, pointed out Mesa and colleagues. "This observation implies that these disease features are not altered by the interventions (phlebotomy, HU) or the presence of splenomegaly."

Despite advances in therapy, the PV symptom burden remains undermanaged, with symptoms such as fatigue, pruritus, night sweats, bone pain, fever, and undesired weight loss resulting in poor quality of life, noted the investigators. Palpable splenomegaly is one of the worst offenders since it contributes to early satiety, bloating, pain, portal hypertension, weight loss, and exacerbation of cytopenia.

Although the symptom burden of patients with PV remains "unacceptably high," results from emerging therapies such as histone deacetylase (HDAC) inhibitors and heat-shock protein-90 (HSP-90) inhibitors, which are currently under investigation in PV, "are anxiously anticipated," said Mesa and colleagues. Such therapies could potentially reduce phlebotomy requirements, protect against vascular events, improve the symptomatic burden, and offer protection against disease transformation, they said.

Direct comparisons between patients in this study and the population represented in the RESPONSE trial are limited, said the investigators.

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